In these days, narcotic analgesic agents such as morphine, nonnarcotic analgesic agents such as NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) have been mainly used as an analgesic agent. However, the use of the narcotic analgesic agent is strictly limited because of its tolerance/addiction or other severe side-effects, and the NSAIDs are not effective against severe pain and also cause upper gastrointestinal disorders or liver toxicities with a high possibility by long-term administration thereof. Therefore, it has been desired to develop a novel analgesic agent that exhibits higher analgesic action with fewer side-effect. Furthermore, an analgesic agent that exhibits a fully-satisfied efficacy for neuropathic pain such as diabetic neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, and HIV-multiple neuropathic pain had not been found yet, and thus it has been expected to develop a useful medicament for treating such diseases.
Capsaicin [(E)-8-methyl-N-vanillyl-6-nonenamide] which is contained in the juice of chili peppers is not used only as a spice, but also known as a material exhibiting analgesic action and anti-inflammation action. In addition, civamide [(Z)-8-methyl-N-vanillyl-6-nonenamide] which is a geometrical isomer of capsaicin is also known as a material exhibiting analgesic action. It has been thought that capsaicin acts specifically on an especial receptor in the primary afferent sensory neuron (mainly C-fiber: capsaicin sensitive neuron) to induce analgesic action and anti-inflammation action as well as strong irritancy (pain) Recently, the receptor was cloned and named as vanilloid receptor subtype 1 (VR1) [Nature, 389, 816 (1997)]. After that, the receptor was classified into TRPVs, one of the TRP (transient receptor potential) superfamily, and is also called TRPV1 [Annu. Rev. Neurosci., 24, 487 (2001)].
TRPV1 is thought to be a high Ca2+-permeable cation channel with six-transmembrane domains according to the amino acid sequence thereof and thus it is supposed that TRPV1 is activated by not only a capsaicin-like compound, but also by heat stimulation, proton, etc., and that TRPV1 is related with various type of pain. When capsaicin acts on TRPV1 in the primary afferent sensory neuron; the cation channel thereof is opened, the membrane is depolarized and then neuropeptides such as Substance P are released, then pain is caused. The reason why capsaicin has been actually used for the treatment of pain such as diabetic neuropathy and rheumatoid arthritis in spite of the painful irritancy of capsaicin is thought to be because capsaicin continuously has TRPV1 cation channel open and thereby the sensory neuron becomes non-reactive for pain (desensitization) [Pharmacol. Rev. 51, 159 (1999)].
Thus, it is thought that a capsaicin-like compound (TRPV1 agonist) can exert analgesic effect via new pharmaceutical mechanism (desensitization of capsaicin-sensitive sensory neuron) that is completely different from that of conventional analgesic agents. Therefore, a capsaicin-like compound is expected to become a useful medicament for treating neuropathic pain or other various types of pain caused by various diseases such as rheumatoid arthritis and osteoarthritis, which are not fully cured with existing analgesic agents.
In the U.S., now an analgesic agent comprising capsaicin has been sold as a cream formulation. However, the capsaicin cream formulation is disadvantageous in its strong painful irritancy just after administered. Therefore, it has been especially desired to develop a medicine for treating neuropathic pain or other types of pain such as rheumatoid arthritis and osteoarthritis, which has the capsaicin-like mechanism and can exert a sufficient analgesic effect with low irritancy.
In addition, it is thought that a compound having the capsaicin-like pharmacological mechanism is useful as a medicament for treating pruritus that is relevant disease to the primary afferent sensory neuron(C-fiber), allergic and nonallergic rhinitis, overactive bladder, stroke, irritable bowel syndrome, respiratory disease (such as asthma/chronic obstructive pulmonary disease), dermatitis, mucositis, gastric/duodenal ulcer and inflammatory bowel syndrome.
Furthermore, it is also thought that a compound having the capsaicin-like pharmacological mechanism may be useful as a medicament for treating obesity, since it is reported that capsaicin can promote the adrenaline secretion to exhibit an anti-obesity activity [Pharmacol. Rev., 38, 179 (1986)]. In addition, it is also thought that the compound may be useful as a medicament for treating diabetes, since it is reported that diabetic rats were improved at the insulin resistance by the treatment for capsaicin [Eur. J Endocrinol., 153, 963, (2005)].
WO 02/100819 discloses that N-arylphenylacetamide derivatives has an analgesic action, however, the derivatives are quite different in chemical structure from the compound (I) of the present invention, namely, it is essential that the compound of the present invention is bound to cyclohexyl or cyclohexenyl group on the nitrogen atom of the acetamide, while it is essential that the compounds of the reference is bound to aryl such as phenyl on the corresponding position.
In addition, Arzneim.-Forsch., 25, 1877 (1975) discloses that the following compound exhibits a little lower irritancy than capsaicin.
And, Arzneim.-Forsch., 26, 33 (1976) (page 35, left column, lines 10 to 14; and FIG. 4) discloses that said compound exhibits a strong stimulatory but it exhibits a weak desensitization. Further, WO 92/18463 (Example 127) discloses N-substituted phenylacetamide compound having the following structure.
However, the above two compounds are different from the below-mentioned present compound of the formula (I) from the viewpoints of the chemical structure of the substituent on the cyclohexane ring and also the pharmacological activity, i.e. the above two compounds exhibits little analgesic effect that the compound of the invention exhibits.